Our long-range goal is to develop immunoprophylaxis against maternal HIV-1 transmission by active and passive vaccination. Here, we propose to study passive immunoprophylaxis with combinations of human neutralizing monoclonal antibodies (mAbs) directed against different HIV-1 Env epitopes in rhesus macaque models that mimic intrapartum and in utero infection. We will challenge with SHIV-89.6P, a chimeric virus that contains tat, rev, vpu and env of a primary HIV-1 isolate, 89.6, in a simian immunodeficiency virus backbone. The Specific Aims are to: 1. Determine whether human mAbs that neutralize primary HIV-1 strains inhibit SHIV-89.6P synergistically when used in combination. 2. Perform pharmacokinetic studies with the most potent mAb combination in pregnant macaque dams and in their offspring. Neutralizing mAbs levels will be measured in maternal blood, amniotic fluid, cord blood and in neonatal mucosal secretions after passive therapy of pregnant macaque dams and newborns. 3. Test whether the most potent triple combination of neutralizing mAbs can protect neonatal macaques against intravenous (i.v.) SHIV-89.6P challenge. We will enroll 3 groups of 4 pregnant dams and their offspring. Group 1 animals will not be treated. Group 2 offspring will receive the mAb combination prenatally (by passive therapy of the pregnant dams) as well as after birth; and group 3 offspring will be given mAbs only postnatally. All 12 neonates will be challenged i.v. on day 1 of life with 10 50 percent animal infectious doses (AID50-i.v.) of SHIV-89.6P. 4. Test whether the most potent combination of human neutralizing mAbs can protect neonatal macaques against mucosal SHIV-89.6P challenge. A similar experimental design will be employed as described for Specific Aim #3. Neonates will be challenged orally (po) at birth with cell-free SHIV-89.6P (10 AID50-po). 5. Test whether the most potent combination of human neutralizing mAbs can protect macaque fetuses against intra-amniotic fluid challenge with SHIV-89.6P during the late 3rd trimester. Passive immunoprophylaxis will be given at weekly intervals during gestation; control dams will be left untreated. Cell-free virus will be instilled into the amniotic fluid under ultrasound guidance. The proposed experiments are highly significant because they allow a direct evaluation of human neutralizing mAbs directed against primary HIV-1 strains in primates. Data generated from this work can be translated into human clinical trials aimed at preventing maternal HIV-1 transmission.